Multiple organ failure (MOF) is a major problem following hemorrhagic shock. Its etiology has remained elusive, but sepsis seems to play an important role in its pathogenesis. This project will focus on the role of the permeability barrier of the intestinal epithelium to the translocation of enteric bacteria and endotoxin in response to hemorrhagic shock as the possible source of sepsis in MOF. There is strong evidence that the injured epithelium will allow permeation by intestinal bacteria. Furthermore, it is known that hemorrhagic shock is associated with ischemia of the bowel wall and activation of oxygen-derived free radicals upon the re-establishment of blood flow. The precise relationships between the magnitude of shock and its duration and the extent of tissue injury is not known. Furthermore, the role of oxygen free radicals in this process has not been fully elucidated in hemorrhagic shock nor have the morphologic consequences been examined in detail at the ultrastructural level. Studies in this project will use a hemorrhagic shock model in rats and will assess the important question of how enteric bacteria actually pass (i.e. translocate) from the lumen of the gut to the portal circulation. This problem will initially be approached by identifying the time relationships between the appearance of morphologic changes within the epithelium of the gut and the identification of enteric organism and endotoxin within the substance of the liver, spleen, and mesenteric lymph nodes after shock and resuscitation. Experiments will be performed To attempt to distinguish whether or not epithelial cell damage must occur before the onset of portal bacteremia or whether a disruption in the tight junctions between cells is sufficient for this to occur. Once the relationship between hemorrhagic shock, reperfusion, epithelial injury, and bacterial translocation has been elucidated, the role of oxygen free radicals in this process will be examined in a systematic manner. The results of these experiments should clarify the relationships between reperfusion injury after hemorrhagic shock, oxygen free radical production, and how enteric bacteria gain entrance to the splanchnic circulation under these experimental conditions. Such studies should provide valuable information concerning the role of intestinal injury in the pathogenesis of MOF and thereby provide a rational basis for its clinical prevention and treatment.